Abstract
We aimed to investigate whether periconceptional maternal folate status affects human embryonic cerebellar size and growth trajectories. In a prospective periconceptional cohort participants filled out questionnaires and received weekly transvaginal 3D-ultrasounds between 7+0 and 12+6 weeks gestational age (GA). Viable non-malformed singleton pregnancies were selected for cerebellar measurements; transcerebellar diameter, (TCD), left and right cerebellar diameters (LCD, RCD). Linear mixed models were performed to estimate associations between questionnaire data on the timing of maternal folic acid supplement initiation and longitudinal cerebellar measurements as a function of crown-rump length (CRL) and GA. Maternal red blood cell folate concentrations were analysed before 8 weeks GA to validate the associations. A total of 263 serial high quality three-dimensional ultrasound scans of 135 pregnancies were studied. Preconceptional compared to postconceptional initiation of folic acid use was associated with slightly larger cerebellar diameters per millimetre increase of CRL (TCD: β = 0.260mm, 95%CI = 0.023–0.491, p<0.05; LCD: β = 0.171mm, 95%CI = 0.038–0.305, p<0.05; RCD: β = 0.156mm, 95%CI = 0.032–0.280, p<0.05) and with proportional cerebellar growth (TCD/CRL:β = 0.015mm/mm, 95%CI = 0.005–0.024, p<0.01; LCD/CRL:β = 0.012mm/mm, 95%CI = 0.005–0.018, p<0.01; RCD/CRL:β = 0.011mm/mm, 95%CI = 0.005–0.017, p<0.01). Cerebellar growth was significantly highest in the third quartile of maternal red blood cell folate levels (1538–1813 nmol/L). These first findings show that periconceptional maternal folate status is associated with human embryonic cerebellar development. Implications of these small but significant variations for fetal cerebellar growth trajectories and the child’s neurodevelopmental outcome are yet unknown and warrant further investigation.
Highlights
Last decades our understanding of the complex functions of the human cerebellum has expanded immensely
Because this study aimed to investigate the initiation of periconceptional maternal folic acid supplement intake in pregnancies ending in live births without congenital malformations, we excluded pregnancies ending in miscarriages, ectopic pregnancy and termination of pregnancy or pregnancies with adverse foetal outcome including minor and major congenital malformations, foetal or neonatal death
This study shows increased, albeit slightly, embryonic cerebellar diameters and proportional cerebellar growth trajectories in ongoing non-malformed pregnancies in a tertiary hospital setting when maternal folic acid supplement use was initiated before conception compared to post conception
Summary
Last decades our understanding of the complex functions of the human cerebellum has expanded immensely. Previous literature demonstrated cerebellar involvement in motor and non-motor functions including perception, cognition and emotion [1,2]. Prenatal studies of the cerebellum have mainly been focussing on abnormal cerebellar development and morphology in the second half of pregnancy when ultrasonography landmarks of development can be visualized [3,4,5]. Ultrasound measurements of embryonic structures are more accessible through the improvements of ultrasound techniques. Growth charts of embryonic brain structures including the cerebellum were created with measurements performed between 7+0 and 12+6 weeks of gestation using three-dimensional ultrasound and virtual reality ultrasound visualization [6]. Three-dimensional techniques provide very precise information on variations in first trimester cerebellar growth trajectories
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